The goal of this project is to use rat models of emotional reactivity and social stress to test the function of novel candidate genes that arise from microarray studies in human postmortem brains of subjects who suffered from severe mood disorders (major depression and bipolar illness). In this proposal, we develop a specific hypothesis and describe the strategy that will be used to implicate a family of novel candidates in mood and affect. The human microarray studies (described in the Overview and in Project 1) pointed to the family of fibroblast growth factors (FGF's) and their receptors as being altered in frontal cortical regions of severely depressed patients relative to control subjects. This change in gene expression was not seen in the brain of bipolar subjects. The FGF family has been implicated in the control of development and differentiation of the brain and in neurogenesis. However, there was little evidence implicating this family in the control of emotional reactivity, stress responsiveness or mood disorders. The array findings have led us to the specific hypothesis that the FGF family is involved either in the etiology or the expression of severe depression. In order to test this hypothesis, we plan to use rats that have been screened for differential responsiveness to stress and anxiety-like situations (High Responders and Low Responders). This allows us to investigate the connection between individual differences in emotionality and anxiety-lake behavior and this gene family. In addition, these animals will either be handled (controls) or subjected to social defeat conditions (stress), which we have shown to activate the same neural pathways engaged by depression in humans. Using this animal model, we plan to address the following questions: 1) Do high responders and low responders differ in the expression of FGF-related genes, either basally or following social defeat? 2) Do various classes of antidepressants have any effects on the expression of the FGF genes, either in control or in socially defeated animals? 3) If we administer members of the FGF family to newborn rats, can we implicate them in hippocampal morphology and alterations in neurogenesis, and can we link these potential alterations to change in emotionality or stress reactivity? Together, these studies serve as a prototype for testing the potential function of genes that were not previously implicated in the severe mood disorders but whose expression is significantly altered in the brain of depressed or bipolar individuals. This will allow us to extend our understanding of the fundamental molecular and neuralmechanisms associated with mood disorders and to develop novel targets for treatment and prevention of these devastating illnesses.